NEW YORK (GenomeWeb News) – By developing a gene expression network that incorporates information on gene interactions, co-regulation, and function, an American and Australian research team has discovered age-related gene expression differences in individuals with schizophrenia.

The researchers compared networks created from post-mortem prefrontal cortex brain region gene expression data for dozens of individuals with and without schizophrenia, creating individual networks for the case, control, and combined groups. Along with general differences in the expression of specific gene groups or “modules,” the team also identified groups of genes that were expressed differently with age, suggesting altered gene regulation — including a failure to curb the expression of some genes with age — may contribute to schizophrenia.

“[W]e hypothesize that, at least a proportion of disease pathogenesis results from a failure of normal age-related down-regulation of gene expression related to neuronal development and dopamine-related signaling,” senior author Elizabeth Thomas, a molecular biology researcher at the Scripps Research Institute, and colleagues wrote in the journal Genome Research. “These findings illuminate a novel molecular basis for schizophrenia that should facilitate diagnosis, prognosis, and therapeutic considerations.”

Schizophrenia is a complex psychiatric condition that’s thought to involve both genetic and environmental risk factors, Thomas and her co-workers explained. While past gene studies have turned up a wide range of genes with altered expression in schizophrenia, such individual gene expression changes offer a limited understanding of schizophrenia biology, the team argued.

Instead, the researchers opted for a network approach, creating modules based on co-expression data, genetic interactions, and functional information for the gene products.

“[T]he greatest molecular variation distinguishing subjects with schizophrenia from controls occurs at the level of collective changes in gene expression within functional networks and the differential effects of aging on key biological systems,” they wrote. “The power to detect these changes is dramatically improved by network co-expression analysis, which can reveal small concerted gene expression changes that may not reach individual gene-level significance due to multiple testing issues.”

The gene expression networks developed for the study brought together prefrontal cortex expression data on 13,012 genes from two post-mortem studies of individuals between 19 and 81 years old — including 47 schizophrenia patients and 54 healthy controls. For each individual, gene expression was assessed using either the Affymetrix Human Genome U133 Plus 2.0 array or the Affymetrix Human Genome U951 array.

Overall, the researchers found that the case network, which contained 2,058 genes, and the control network, which contained 2,812 genes, had overlapping connections, with similar groups of genes being co-regulated.

When they looked at the sorts of genes that were differentially expressed in the schizophrenia network, the team detected significant expression differences in five groups of genes. The affected groups housed genes involved in everything from metabolism and energy production to neuron development and differentiation to chromatin assembly and transcription.

The team also found differences in the gene expression networks when they took individuals’ age into account. For instance, the expression of three groups of genes decreased with age in the control group but not in the schizophrenia group.

One of these groups included 30 genes involved in nervous system development, neuron differentiation, and neurotransmitter receptors, and more, leading the researchers to suspect that “normal age-related decreases in genes related to [central nervous system] developmental processes, including neurite outgrowth, neuronal differentiation, and dopamine-related cellular signaling, do not occur in subjects with schizophrenia during the aging process.”

On the other hand, another three groups of genes — including genes involved in lipid metabolism, immunological disease, and gene expression — showed age-related alterations in expression in case but not control groups.

Based on these findings, those involved suggest that the pathogenic trigger for schizophrenia may not necessarily be tied solely to developmental processes occurring early in life, but may involve differences that span the individual’s lifetime. That, in turn, hints that schizophrenia treatments targeting genes that are differentially expressed and regulated may have to account for age.